Development of a Multimodal Approach for Early Identification of Pancreatic Cancer

1. ABSTRACT

This study aims to create a multimodal strategy that combines imaging methods and biomarkers for the early detection of pancreatic cancer. By enhancing pancreatic cancer detection’s sensitivity, specificity, and accuracy, this strategy hopes to promote early intervention and enhance patient outcomes.

2. KEYWORDS

Pancreatic cancer, Multimodality, Early identification of Pancreatic Cancer

3. INTRODUCTION

Early identification of pancreatic cancer is difficult since symptoms are sometimes ambiguous or nonexistent until the disease has advanced.

While Imaging techniques like Computed tomography (CT SCAN), Magnetic Resonance Imaging (MRI), and Endoscopic Ultrasound (EUS) can help with early diagnosis, they might not be precise and may have restrictions on accuracy and specificity. Tumor marker testing includes CA 19-9, a blood-based tumor marker, and KRAS gene mutations which are often common in pancreatic cancer patients. ERCP is also frequently used to examine the pancreas and bile ducts using endoscopy and X-ray imaging. It can aid in the detection of blockages, abnormalities, or malignancies in the pancreas. To improve pancreatic cancer early detection tools, more study and development are necessary. To improve outcomes for those who are at risk of or impacted by the disease, early detection of pancreatic cancer is, in general, a multidisciplinary effort including healthcare professionals, researchers, patients, advocacy groups, and numerous stakeholders.

There are still several unaddressed areas in the identification of pancreatic cancer despite substantial research and clinical efforts, and further study is required to enhance early detection and diagnosis. Issues including the absence of reliable biomarkers, such as CA 19-9  have low sensitivity and specificity, rendering them unsuitable for accurate early detection. Imaging challenges such as the absence of standardized screening protocols and limited knowledge of early symptoms further hinder early identification. Especially in the early stages of the disease, imaging procedures such as CT scans, MRIs, and endoscopic ultrasounds (EUS) can be inconclusive. It is crucial to create advanced and accurate imaging techniques.

The main objective of this article is to find and validate particular biomarkers that indicate pancreatic cancer early on, such as proteins, nucleic acids, or metabolites. It is possible to use these biomarkers for early diagnosis and screening as well as improving the sensitivity and specificity of imaging modalities for detecting pancreatic cancer tumors in their early stages.

4. LITERATURE REVIEW

The mortality rate surrounding pancreatic cancer is 98.8%. Even with modern technology and medical intervention and therapies, little to no effect has taken place on the mortality rate, with multiple factors post-surgery affecting the prognosis, such as microscopic residual disease following curative resection attempts, lymphatic or perineural invasion, metastasis to distant organs, and local lymph nodes being major contributors. 1

50% of animals injected with as few as 100 CD44+CD24+ESA+ cells formed tumors that were histologically identical to the human tumors from which they originated. Pancreatic cancer cells with the CD44+CD24+ESA+ phenotype (0.2–0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with non-tumorigenic cancer cells. 2  Different pancreatic adenocarcinoma cell lines had different expression patterns for the pancreatic cancer stem cell surface markers CD44, CD24, and ESA, and these expression patterns fluctuated depending on the local microenvironment. 3

Since pancreatic cancer is well known for being resistant to conventional chemotherapy and radiation therapy, the identification of pancreatic cancer stem cells and further investigation of the signaling pathways governing their growth and survival may offer novel therapeutic approaches to treat the disease. A small subset of distinct cancer stem cells with a proliferative potential of ~5% of total tumor cells based on cell surface marker expression and more differentiated cancer cells with a limited proliferative potential make up malignant tumors. [Cancer Res 2007;67(3):1030–7]

Among PC biomarkers, carbohydrate antigen 19–9 (CA 19–9) is the most commonly utilized. However, CA19-9 is not the best biomarker for screening and early identification of PC due to its relatively low sensitivity and specificity (70–90% and 68–91%, respectively) for PC18 diagnosis. Its primary therapeutic use is as a marker for tracking medication response and progression. 4

It is commonly known that a buildup of somatic gene mutations, including loss-of-function mutations in tumor suppressor genes (such as TP53/p53, SMAD4, BRCA2, and CDKN2A/p16) and gain-of-function mutations in proto-oncogenes (like KRAS), is what causes PC. 5

Based on patterns of chromosomal structural variation, PC is divided into four subtypes with potential clinical value and outcome: stable, locally rearranged, dispersed, and unstable. These subtypes are identified using whole-genome sequencing and copy number variation analysis.

The driver mutations for both familial and sporadic PC are KRAS, CDKN2A, TP53, and SMAD4. However, familial cases are linked to inherited germline mutations that raise the risk of PC significantly. These include ATM, STK11, PRSS1, BRCA2, BRCA1, PALB2, CDKN2A/p16, DNA mismatch repair genes (like MLH1 and MSH2), and other candidate genes like BUB1B, CPA1, FANCC, and FANCG. 6

There are both inherited and non-inherited risk factors for pancreatic cancer. The following conditions, both hereditary and non-hereditary, have been connected to an increased risk of pancreatic cancer, the hereditary risks being:

1. A strong family history of pancreatic cancer is a defining feature of familial pancreatic cancer (FPC). A person’s risk is higher if they have two or more first-degree relatives—parents or siblings—who have had pancreatic cancer. Genetic alterations could be involved with FPC. 7
2. A number of inherited genetic variants, including PRSS1, raise the possibility of developing chronic pancreatitis, a disorder linked to a higher risk of developing pancreatic cancer. 8
3. Peutz-Jeghers syndrome, a gastrointestinal system disorder, develops polyps as a characteristic of this genetic illness. People who have Peutz-Jeghers syndrome are more likely to get pancreatic cancer, among other cancers. 9
4. In addition to raising the chance of colorectal cancer, Lynch syndrome (also known as Hereditary Non-Polyposis Colorectal Cancer, or HNPCC) also raises the risk of other cancers, such as pancreatic cancer. 10
5. Mutations in the BRCA1 or BRCA2 genes are mainly linked to ovarian and breast cancers, but they also raise the risk of pancreatic cancer in those who carry them. 11
6. Mutations in the PALB2 gene have been linked to an increased risk of pancreatic and breast cancer. 12

The non-hereditary risks are:

1. The majority of pancreatic cancer cases are detected in adults over 45, and the risk increases with age.
2. One of the main risk factors for pancreatic cancer is cigarette smoking. When it comes to risk, smokers are far more risky than non-smokers.
3. Long-term diabetes has been linked to an increased risk of pancreatic cancer, especially type 2 diabetes.
4. Obesity or being overweight increases the chance of pancreatic cancer.
5. A diet deficient in fruits and vegetables and heavy in processed and red meat may raise the risk of pancreatic cancer.
6. Pesticide exposure at work is one type of chemical exposure that may increase the risk of pancreatic cancer.

Exosomes are tiny vesicles that are released by a variety of cell types, including cancer cells. They are involved in molecular information transfer and cell-to-cell communication. Exosomes have drawn attention in the context of pancreatic cancer due to their possible role in a number of cancer progression factors, such as immune evasion, treatment resistance, metastasis, and tumor growth. A wide range of substances, including proteins, lipids, and nucleic acids (including microRNAs), can be transported and transferred by exosomes released by pancreatic cancer cells to other cells in the surrounding tumor microenvironment. The growth and aggressiveness of pancreatic cancer can be influenced by these exosome-mediated transfers. Pancreatic cancer-specific molecular markers may be present in exosomes. Exosomes are being investigated by researchers as possible indicators for tracking the onset of illness and detecting its progression.  15

Stool, urine, and saliva are examples of bodily fluids and excretions that are typically enriched with specific biomarkers that can be utilized to identify PC. Given that the small intestine secretes between 800 and 1,500 milliliters of pancreatic juice daily, fecal testing for PC patients may be more sensitive than blood-based techniques. 16 17 18

5. RESEARCH METHODOLOGY

Assemble a varied dataset comprising the following: medical images (MRIs, CT scans, ultrasounds, and endoscopic images), clinical information (symptoms, medical history, and patient demographics), biomarker information (tissue, blood, or urine samples), and genetic information (such as genetic alterations linked to pancreatic cancer), ensuring that data collection adheres to ethical standards and is uniform.

The primary research method for this study is a literature review and the use of randomized controlled trials (RCTs) or cohort studies to evaluate the multimodal approach’s efficacy.

The first step toward creating a “zero-constraint” environment is to identify and classify constraints using an organized method. To increase the precision and efficacy of detection, this study will first examine various forms of limitations in the early identification of PC and its characteristics. To identify constraints, a classification algorithm for constraint factors will be constructed based on this understanding.

The second stage of the study would be establishing the study population, including the eligibility requirements, taking into account variables such as gender, age, family history, and risk factors for pancreatic cancer, as well as standardizing and preparing data to guarantee interoperability and consistency across various modalities. Research and collection of data regarding biomarkers, epigenetic markers, exosomes, and mutations in BRCA1 and BRCA2 genes, as well as KRAS mutations, will be studied in this stage.

The next stage of this study would be to determine how the data from many modalities will be merged, such as by applying fusion techniques, machine learning models, or artificial intelligence algorithms. Assessment of the multimodal approach’s clinical usefulness as well as taking into account how it affects patient outcomes and early detection rates.

6. RESULTS

It may be possible to use epigenetic markers, such as changes in chromatin structure, microRNA (miRNA) levels, and promoters, to improve PC early diagnosis. Modifications include DNA repair genes and tumor suppressor genes losing their functions, as well as methylation-regulated oncogenes gaining their functions. 13  14  Among epigenetic markers, DNA methylation is the most well-known. Subsequent to the first discovery of widespread hypomethylation in human cancers, hypermethylated tumor-suppressor genes were found, and more recently, it was shown that DNA methylation inactivates microRNA (miRNA) genes.

7. DISCUSSION

There is unquestionable evidence that the survival rate can be significantly increased by presymptomatic identification of the earliest-stage PC. Moreover, survival may be increased even if symptoms-bearing patients had a shorter time to diagnosis. Identifying PCs before an invasion is one of the main objectives of the experts attending the summit. When instances are identified early enough to be treated, this will have a major effect on survival. Both at the precancerous and early T1 cancer stages, the protracted presymptomatic dwell time may offer a comparatively large window of opportunity for screening identification.

Molecular imaging has become a promising method for the identification of tiny lesions, which could lead to a diagnosis at a much earlier stage than currently possible. The advantage of molecular imaging is that it can distinguish molecular variations, rather than physical ones, between tumor and normal or CP tissue. The ability to integrate molecular imaging with traditional imaging modalities, such as fluorescence endoscopy, molecular ultrasound, or PET/MRI, may significantly impact patient outcomes.

Currently, there are no successful non-invasive detection techniques available. Each imaging test has advantages of its own and is used in all facets of PC clinical management. These tests include US, CT, MRI, EUS, ERCP, and FDG-PET. When it comes to PC cases smaller than 10 mm, EUS has a greater diagnostic rate than CT or other modalities, but MDCT is still recognized as the most useful imaging method for PC diagnosis. Certain biomarkers have shown better sensitivity and specificity than CA19-9 thus far. The most promising biomarker appears to be miRNA profiling in particular because miRNAs are stable and simple to find. We believe that liquid biopsy techniques like ctDNA and exosomes will also find widespread use as detection technology becomes more straightforward.

8. CONCLUSION

Throughout the entire process of diagnosing and treating pancreatic cancer, a multidisciplinary partnership combining the therapeutic departments (oncology, gastroenterology, and surgery) as well as the diagnostic departments (radiology, laboratory medicine, and ultrasound) is essential. Therefore, to speed up the production of scientific research and the transformation of medicine, it is essential to improve interdisciplinary integration and collaboration among various disciplines.

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